tbuckley/cabot-search huggingface dataset:
Abstract LB334: Assessment of the potential of graphene oxide as an antigen delivery platform for cancer immunotherapy
Authors: Sorayut Chattrakarn, Grace Mallett, Helen Parker, Neus Lozano, Kostas Kostarelos, Andrew S. MacDonald
Journal: Cancer Research (2023)

Abstract Introduction: Novel cancer immunotherapies are urgently needed due to a lack of definitive treatments, as well as toxicity and cost of current therapies. 2-dimensional carbon graphene oxide (GO) nanomaterials provide a large surface area, high protein loading efficiency and good biocompatibility, as well as being inexpensive. Given these properties, we investigated whether and how GO could be an effective antigen delivery system for targeted cancer immunotherapies. Methods: GO was non-covalently complexed with the model antigen ovalbumin peptide (OVA257-264) and the immunostimulant and toll-like receptor 3 agonist polyinosinic:polycytidylic acid (Poly (I:C)). We examined innate and adaptive immune responses after subcutaneous injection of GO complexes by histology and flow cytometry. Results: We found that GO without Poly (I:C) had a very limited immunogenic potential. In contrast, GO complexed with Poly (I:C) significantly increased immune cell recruitment to the injection site, and enhanced activation and migration of dendritic cell subsets (cDC1s and cDC2s) in skin-draining lymph nodes 24 hours after injection. Additionally, we found that GO complexed with Poly (I:C) dramatically enhanced OVA-specific CD8+ T cell expansion and cytotoxic potential in both spleen and skin-draining lymph nodes 7 days after subcutaneous complex administration to mice which had previously been injected intravenously with traceable, OVA-specific (OT-I) CD8+ T cells. Conclusion: Our results have revealed the immunomodulatory potential of GO when complexed with Poly (I:C) by attracting immune cells to the injection site and augmenting antigen-specific cytotoxic responses both locally and systemically. Ongoing work is determining the anti-tumor potential of this approach, and potential mechanisms by which GO complexes might limit tumor progression. Citation Format: Sorayut Chattrakarn, Grace Mallett, Helen Parker, Neus Lozano, Kostas Kostarelos, Andrew S. MacDonald. Assessment of the potential of graphene oxide as an antigen delivery platform for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB334.
Abstract LB202: Obesity-trained C1q+ macrophages compromiseT cell anti-tumor immunity
Authors: Tao Zhang, Shimeng Liu, Myles Brown
Journal: Cancer Research (2023)

Abstract Adipose tissue in the mammary gland undergoes dramatic remodeling during obesity and is involved in ﻿numerous metabolic diseases. ﻿However, how obesity-driven remodeling in adipose tissue regulates anti-tumor immunity remains unclear. Here we provide the detailed cellular atlases of mouse mammary fat pad and tumor at single-cell resolution in lean and obese mice. By leveraging scRNA-seq, we found that high-fat feeding causes a marked increase of macrophage in adipose tissue. ﻿Interestingly, a subset of macrophages expressing high levels of C1q complex genes is accumulated in obese subjects. We found that glucocorticoid may as a key regulator of C1q+ macrophage identity. Synthetic glucocorticoid, Dexamethasone, triggers C1q expression in macrophages. We found that C1q+ macrophage derived C1q complex could suppress CD8+ T cell response, thus fueling breast cancer progression. In mouse TNBC tumor, we uncovered a specific inflammatory responsive tumor subset in obese tumors with high CCR2 ligand expression. Obesity-induced TNFα exposure triggers of breast cancer cells reprogramming and CCR2 ligand production. Consequently, CCR2 ligands promote macrophage into tumor. Moreover, depletion of macrophages by anti-CSF1R suppresses tumor growth in obese mice. Our findings define a novel fundamental mechanism of C1q+ macrophage involved in anti-tumor response in obesity. Citation Format: Tao Zhang, Shimeng Liu, Myles Brown. Obesity-trained C1q+ macrophages compromiseT cell anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB202.
Abstract LB048: AR-targeted linked-read sequencing reveals complex AR structural variants in CRPC tumors
Authors: Andrej Zivanovic, Sarah A. Munro, Jeffrey T. Miller, Yingming Li, Courtney N. Passow, Scott M. Dehm
Journal: Cancer Research (2023)

Abstract Inhibition of the androgen receptor (AR) transcription factor is the mainstay therapeutic strategy for systemic prostate cancer. However, development of a resistance phenotype termed castration resistant prostate cancer (CRPC) enables disease progression that underlies virtually all prostate cancer mortality. In the majority of CRPC, AR is transcriptionally re-activated in part due to accumulation of numerous alterations in the AR gene. These genomic alterations include missense mutations in exons that encode the ligand binding domain of AR, amplification of the AR gene body and/or an upstream transcriptional enhancer, and AR structural variants (SVs) resulting from inaccurate repair of DNA double strand breaks. In CRPC patient samples, these AR genomic alterations co-occur within tumors, which makes elucidating the fitness contribution of each alteration difficult. While short-read DNA sequencing has allowed for characterization of these events, they are underpowered to preserve linkage information. To address this challenge, we performed AR-targeted linked-read DNA-sequencing of CRPC cell line and patient derived xenograft (PDX) models with the goal of resolving sub-clonal and complex AR SVs. This approach confirmed the heterogeneity of AR SVs in these PDXs, including phased AR SVs that can be traced back to a single high molecular weight DNA molecule. These phased AR SVs were consistently found to co-occur in CRPC specimens with amplification of AR. Our results define a new class of AR SVs where multiple rearrangements co-occur on amplified DNA molecules to yield a complex array of AR gene structures in CRPC. Citation Format: Andrej Zivanovic, Sarah A. Munro, Jeffrey T. Miller, Yingming Li, Courtney N. Passow, Scott M. Dehm. AR-targeted linked-read sequencing reveals complex AR structural variants in CRPC tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB048.
Abstract LB263: An <i>in vivo</i> unbiased screen identifies clathrin adaptor protein complex-2 as a novel tumor suppressor
Authors: Seth Parker Zimmerman, Christopher M. Counter
Journal: Cancer Research (2023)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly lethal. It is thus imperative to find new therapeutic approaches to treat this disease. While whole genome CRISPR/Cas9 screens have successfully identified new vulnerabilities in PDAC cell lines, it is becoming increasingly clear that cell culture do not faithfully recapitulate the complex nature of tumorigenesis in vivo, and hence may fail to identify the full spectrum of potential therapeutic targets to be explored in this devastating disease. As previous screens we performed identified phosphatidylinositol (Ptdlns) metabolism as important for pancreatic cell growth, I generated a custom sgRNA library targeting this entire form of metabolism. To identify vulnerabilities specific to tumor growth, I screened this library in five different human PDAC cell lines grown in culture versus as xenograft tumors. I found that sgRNAs targeting two genes encoding separate subunits of the Adaptor Protein complex-2 (AP2), a regulator of clathrin mediated endocytosis, were negatively enriched in all five PDAC cell lines when grown in culture. In agreement, AP2 subunit genes are considered common essential by DepMap. Paradoxically however, the same sgRNAs were positively enriched in three of these five cell lines when grown as xenograft tumors. This begs the question how the loss of a supposably essential complex behaves like a tumor suppressor and instead enhances tumor growth when disrupted. Here, I will present data that loss of AP2 results in a substantial restructuring the plasma membrane proteome, which in cultured cells results in the loss of iron transport, one of the main functions of this complex, and cell death. Conversely, this restructuring in vivo retains receptors and adhesion proteins on the cell surface, where transcriptome and proteomic analysis indicate enhances proliferative signaling. These data support AP2 promoting cell viability of cultured cells through active iron transport, but suppresses tumor growth in vivo by endocytosing the very receptors needed for tumor growth. Citation Format: Seth Parker Zimmerman, Christopher M. Counter. An in vivo unbiased screen identifies clathrin adaptor protein complex-2 as a novel tumor suppressor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB263.
Abstract LB344: Complement-mediated signaling during cross-presentation of tumor antigen augments T cell responses
Authors: Caryn L. Bird, Gabriela A. Pacholczyk, Theodore S. Johnson
Journal: Cancer Research (2023)

Abstract Production of complement C3a and C5a locally at the immune synapse by activated dendritic cells (DCs) enhances T cell responses in multiple experimental models. Complement signaling through cognate C3a receptor (C3aR) and C5a receptor (C5aR) modulate effector T cell stability, proliferation and differentiation. We have previously shown that complement C3 plays a mechanistic role in driving synergistic anti-tumor effects of blocking indoleamine 2,3-dioxygenase (IDO) during radiation and chemotherapy in a murine brain tumor model that expresses the gp10025-33 peptide antigen. We hypothesize that, when anti-tumor responses are allowed to happen, complement C3 production by local DCs acts as a costimulation factor, operating through C3aR and C5aR on the T cell surface to allow optimal T cell activation and proliferation. To study the role of complement C3 as a costimulation factor during T cell responses against a nominal tumor antigen (gp10025-33 peptide, expressed by B16F10 melanoma), we used T cells from syngeneic pmel-1 mice (TCR transgenic with CD8 T cells that recognize the cross-presented gp10025-33 peptide) co-cultured with gp10025-33 peptide and dendritic cells from either wild-type (WT) or C3-defiecient (C3-KO) mice. In addition, we used in vitro culture conditions where gp10025-33 tumor peptide was in stringent limited supply to model homeostatic conditions of the tumor microenvironment. We found that, when stimulated by DCs from C3-KO mice, pmel-1 CD8 T cells had decreased activation marker expression, proliferation, and cytokine effector function relative to stimulation by DCs from WT mice. Next, we bred pmel-1 mice onto a syngeneic background deficient in receptors for both C3a and C5a complement factors (C3aR-KO/C5aR-KO double knock-out mice). We used CD8 T cells from the resulting mouse strain (pmel-1/C3aR-KO/C5aR-KO) co-cultured with WT DCs to study the role of complement signaling in T cells during responses to tumor antigen. Using the same stringent antigen conditions, CD8 T cells from the pmel-1/C3aR-KO/C5aR-KO mice had decreased activation marker expression and proliferation, and differences in cytokine function compared to CD8 T cells from the pmel-1 mice. These findings suggest that lack of local complement production by the DCs in the tumor microenvironment may inhibit anti-tumor immune responses, and that complement signaling through C3aR and C5aR on T cells may play an important role during such anti-tumor responses. Citation Format: Caryn L. Bird, Gabriela A. Pacholczyk, Theodore S. Johnson. Complement-mediated signaling during cross-presentation of tumor antigen augments T cell responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB344.
Abstract LB099: Organoid-based drug efficacy evaluation model for immunotherapy
Authors: Boeun Lee, Woo Kyeom Yang, Sarang Kim, Hee-Ra Lee, Donghyeon Kim, Jongman Yoo
Journal: Cancer Research (2023)

Abstract The endogenous immune system of patients are known to be activated through immuno-oncology drug, which activates the patient’s own immune system to target and attack tumors. Due to the relatively low occurrence of side effects and sustained success, these therapeutic techniques have gradually replaced the traditional cancer treatment regimen. The creation of an in-vitro screening platform for pre-evaluating the efficacy of immunotherapeutic drug candidates was highly essential despite the fact that many of the new emerging therapies had failed clinical trials.An in-vitro platform mirroring the interaction between a patient's unique Major Histocompatibility Complex (MHC) and T-cell receptor (TCR) is necessary for predicting the precise efficacy of immunotherapies. The tumor cells' MHC antigen molecule attaches to the T-cell receptor (TCR), allowing T-cells to manifest their tumor-killing activities as a result. The link between immunological checkpoint (ICP) in tumor cells and their receptors in T cells allows tumor cells to evade the effects of T-cell-mediated tumor death.We would like to introduce our "ODISEI" platform, a robust efficacy evaluation tool that enables the recapitulation of a patient's unique immune system, utilizing tumor organoids and PBMC from the same donors. Using PD-1/PD-L1 inhibiting antibodies, the enhanced functionality of our ODISEI platform as an effective evaluation platform for immunotherapy drugs was thoroughly examined. Additionally, we created several ODISEI platforms in order to recreate the precise interactions between tumor organoids and various immune sub-populations (T-cells, macrophages, regulatory T-cells, and dendritic cells). Our ODISEI platforms were validated by utilizing a variety of different drug candidates and evaluating their ability to eradicate tumors upon interaction with various reactive immune cells and tumors. As a result, our highly innovative ODISEI platform can be used to screen a variety of different immunotherapeutic drug candidates and distinguish their precise efficacy. Citation Format: Boeun Lee, Woo Kyeom Yang, Sarang Kim, Hee-Ra Lee, Donghyeon Kim, Jongman Yoo. Organoid-based drug efficacy evaluation model for immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB099.
Abstract LB003: BI 907828: A highly potent MDM2-p53 antagonist suitable for intermittent dose schedules
Authors: Andreas Gollner, Patrizia Sini, Dorothea Rudolph, Harald Weinstabl, Juergen Ramharter, Ulrike Weyer-Czernilofsky, Bojana Golubovic, Rolf Grempler, Alejandro Pérez Pitarch, Reinhard Sailer, Darryl B. McConnell, Norbert Kraut
Journal: Cancer Research (2023)

Abstract The E3 ligase MDM2 controls the tumor suppressor function of p53, which is encoded by the TP53gene. Compounds designed to bind to MDM2 preventing its interaction with p53 restore the ability of p53 to combat the pathogenic processes that underly cancer development. It has become clear from early clinical experience that thrombocytopenia represents an on-target, dose-limiting toxicity that may restrict the therapeutic utility of first-generation MDM2 inhibitors. Dosing less frequently, while maintaining efficacious exposure levels, has been proposed as an approach to mitigate side effects and improve the therapeutic window. In this -Late Breaking- session we present the discovery and preclinical evaluation of BI 907828, a highly potent, orally bioavailable and selective molecule binding to MDM2 and preventing its interaction with p53. The compound was designed to have a long half-life to enable intermittent dosing schedules in the clinic where it showed a manageable safety profile in a Phase Ia/Ib, dose-escalation/expansion study and encouraging signs of antitumor activity in patients with advanced DDLPS and WDLPS. BI 907828 is actively investigated in several clinical trials including the Phase II/III Brightline-1 study that aims to evaluate whether it is superior to doxorubicin in the first-line treatment of advanced/metastatic DDLPS. BI 907828 belongs to the class of spiro-oxindole MDM2-p53 antagonists and was discovered starting from an optimized core structure with improved chemical stability. Structure-based medicinal chemistry optimization including rigidification of the scaffold were key to accomplish the desired profile which was tested preclinically in several in vivo MDM2-amplified xenograft models where treatment with BI 907828 showed efficient tumor growth inhibition and regression. Citation Format: Andreas Gollner, Patrizia Sini, Dorothea Rudolph, Harald Weinstabl, Juergen Ramharter, Ulrike Weyer-Czernilofsky, Bojana Golubovic, Rolf Grempler, Alejandro Pérez Pitarch, Reinhard Sailer, Darryl B. McConnell, Norbert Kraut. BI 907828: A highly potent MDM2-p53 antagonist suitable for intermittent dose schedules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB003.
Abstract LB041: EZH2 and ATF6 sense metabolic stress to balance MHC class I antigen presentation in melanoma
Authors: Jacob L. Edmondson, Megan R. Reed, Lauren C. Morehead, Billie Heflin, Brian Koss, Alan J. Tackett
Journal: Cancer Research (2023)

Abstract Unleashing the immune anti-tumor response through immune checkpoint inhibitors (ICIs) is a promising strategy to combat many solid-tumor malignancies, including metastatic melanoma. When successful, the anti-tumor response is potent; however, around half of melanoma patients fail to respond to ICIs. Patient responsiveness to ICIs has been characterized by increases in MHC class I (MHC-I) expression driven by increases in oxidative metabolism. Though the harsh conditions of the tumor microenvironment (TME) are known to be immunosuppressive, the specific mechanisms connecting metabolic stress and antigen presentation are not well understood. To recapitulate and investigate the ICI-responsive phenotype in vitro, a model of metabolic remodeling was developed which forces melanoma cells (A375, A101D, B16F10) to metabolically adapt to the absence of glucose. Proteomic profiling indicates a reversible, adaptive phenotype reminiscent of published ICI-responders, and pathway enrichment shows analogous increases in oxidative metabolism and restoration of MHC-I expression. This phenotype, and its impact on MHC-I expression, significantly increases tumor cell sensitivity to T-cell-mediated killing in vitro. Additionally, successful adaptive remodeling of JAK1 and IFNAR1 KO cell lines suggests the metabolism-mediated induction of MHC-I is independent of IFN signaling. Proteomic analysis of three metabolically conditioned melanoma cell lines identified downregulation of the histone methyltransferase EZH2 (Enhancer of Zeste Homolog 2) and the activating transcription factor ATF6 as key determinants of MHC expression. In these studies, we mechanistically explore the control of MHC-I antigen presentation through the transcriptional and post-translational dysregulation of ATF6 and EZH2. Here, we demonstrate that ATF6 overexpression, and thereby activation of the adaptive unfolded protein response (UPR), prevents induction of MHC by EZH2 inhibition. These data suggest EZH2 and ATF6 act to balance MHC-I antigen presentation during metabolic stress whereby loss of EZH2 increases and activation of ATF6 prevents MHC antigen presentation. Additional and ongoing studies coupling EZH2 and ATF6 inhibition will provide crucial insight into this mechanism and have the potential to influence adjuvant therapy development. Citation Format: Jacob L. Edmondson, Megan R. Reed, Lauren C. Morehead, Billie Heflin, Brian Koss, Alan J. Tackett. EZH2 and ATF6 sense metabolic stress to balance MHC class I antigen presentation in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB041.
Abstract LB182: Targeting arginine methylation for improved therapy in triple negative breast cancer
Authors: Yang Li, Daniel J. McGrail, Sharad Awasthi, S. Stephen Yi, Mark T. Bedford, Nidhi Sahni
Journal: Cancer Research (2023)

Abstract Since the discovery of DNA repair deficiency as risk factors for breast cancer, our knowledge of their function in maintaining human genomic integrity and a normal biological function has greatly advanced, ultimately culminating in development of PARP inhibitors that can specifically target patients who harbor these mutations. However, to date PARP inhibitors have demonstrated only modest clinical success as monotherapy in triple-negative breast cancer. In addition, conventional therapies are often coupled with severe toxicity. Therefore, there is a dire need to develop more effective combination therapies. Although there are many existing tools to predict possible actionable targets, it remains challenging to effectively and systematically identify drug combinations for better breast cancer therapeutics. This is because most tumors carry multiple genetic alterations that cannot be suppressed with mono-therapies; and diverse confounding factors such as intra-tumor and inter-tumor heterogeneity exist across patient populations. Our preliminary proteomics study has revealed a new protein mark called arginine methylation as a novel target for breast cancer. We found that inhibition of arginine methylation can sensitize cancer cells for PARP inhibition treatment. We further assessed and validated this actionable and synergistic drug combination in patient-derived xenograft models. Together, our novel target combinations discovered here may serve as important biomarkers to help develop more effective combination therapy. Furthermore, our results help uncover patient-specific signaling mechanisms, a critical step towards precision medicine in breast cancer therapy, which is a benefit and potential long-term outcome. Citation Format: Yang Li, Daniel J. McGrail, Sharad Awasthi, S. Stephen Yi, Mark T. Bedford, Nidhi Sahni. Targeting arginine methylation for improved therapy in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB182.